2014 “ Towards an HIV Cure ” symposium Melbourne
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Transcript of 2014 “ Towards an HIV Cure ” symposium Melbourne
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2014 “Towards an HIV Cure” symposiumMelbourne
Genetically Characterizing the Role of Cell Proliferation in Maintaining Persistent HIV
during Effective HIV TherapySarah Palmer
Westmead Millennium Institute and University of Sydney
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Background
•A diverse repertoire of naive and memory T cells is maintained to defend against new and previously encountered pathogens
•The level of peripheral T cells is closely regulated and is maintained by cellular proliferation and homeostatic proliferation which takes place within the T cell area of the spleen and lymph nodes
•However, T cell proliferation, differentiation and activation have poorly defined effects on the latent HIV reservoir during potent cART
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Objectives of the Study
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Patient 6Treated during chronic infection> 5 years of therapy
PlasmaPre-Therapy - 2004Pre-Therapy - 2005On-Therapy – Time Point 1On-Therapy – Time Point 2
GALT – Effector Memory
GALT – NaiveGALT – Central / Transitional Memory
On-therapy – First Time Point
Peripheral blood – Central / Transitional MemoryPeripheral blood – Effector Memory
Peripheral blood – NaivePeripheral blood – All Memory
On-therapy – Second Time Point
Peripheral blood – Effector Memory
Peripheral blood – NaivePeripheral blood – Central MemoryPeripheral blood – Transitional Memory
GALT – Effector Memory
GALT – NaiveGALT – Central / Transitional Memory
0.005
19 Identical Sequence Expansions2 Identical Sequence Expansions Include Pre-therapy
Identical Sequences Identical sequences during long-term
suppressive therapy>2 genetically identical sequences
Time Point 1 Time Point 2 Time Point 1 Time Point 2Naïve 33% 33% 0% 0%
Memory All 19% N/A N/A N/A
Central/Transitional Memory 18% N/A 27% 0%Central Memory N/A 11% N/A N/A
Transitional Memory N/A 6% N/A N/A
Effector Memory 33% 57% 8% 83%
Cell TypeBlood GALT
Time Point 1: EM vs CTM > 2-fold p = 0.3
Time Point 2: EM vs CM > 11-fold p = 0.001
EM vs TM > 20-fold p < 0.001
33% 57%
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Patient 8Treated during chronic infection>8 years of therapy
PlasmaPre-Therapy - 2000Pre-Therapy - 2002
GALT – Effector Memory
GALT – NaiveGALT – Central / Transitional Memory
On-therapy – First Time Point
Peripheral blood – Central / Transitional MemoryPeripheral blood – Effector Memory
Peripheral blood – NaivePeripheral blood – All Memory
On-therapy – Second Time Point
Peripheral blood – Effector Memory
Peripheral blood – NaivePeripheral blood – Central MemoryPeripheral blood – Transitional Memory
GALT – Effector Memory
GALT – NaiveGALT – Central / Transitional Memory
Lymph node tissue – Effector Memory
Lymph node tissue – NaiveLymph node tissue – Central MemoryLymph node tissue – Transitional Memory
Identical Sequences
Identical sequences during long-term suppressive therapy
27 Identical Sequence Expansions1 Identical Sequence Expansion Includes Pre-therapy
0.01
Time Point 1: EM vs CTM > 2-fold p = 0.2
Time Point 2: EM vs CM > 20-fold p = 0.0001
EM vs TM 7-fold p = 0.01
Time Point 1 Time Point 2 Time Point 1 Time Point 2 Time Point 1 Time Point 2Naïve 24% 22% N/A N/A N/A 17%
Memory All 38% N/A N/A N/A N/A N/A
Central/Transitional Memory 53% N/A 30% 0% N/A N/A
Central Memory N/A 15% N/A N/A N/A 12%Transitional Memory N/A 35% N/A N/A N/A 26%
Effector Memory 73% 79% 6% 17% N/A 61%
Cell TypeBlood GALT LNT
73% 79% 61%
Time Point 2: EM vs CM > 11-fold p = 0.0003
EM vs TM > 4-fold p = 0.02
61%
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Patient 7Treated during chronic infection> 9 years of therapy
PlasmaPre-Therapy - 2002
GALT – Effector Memory
GALT – NaiveGALT – Central / Transitional Memory
On-therapy – First Time Point
Peripheral blood – Central / Transitional MemoryPeripheral blood – Effector Memory
Peripheral blood – NaivePeripheral blood – All Memory
On-therapy – Second Time Point
Peripheral blood – Effector Memory
Peripheral blood – NaivePeripheral blood – Central MemoryPeripheral blood – Transitional Memory
0.005
Identical Sequences
Identical sequences during long-term suppressive therapy
9 Identical Sequence ExpansionsNO Identical Sequence Expansions Include Pre-therapy
Time Point 1 Time Point 2 Time Point 1 Time Point 2Naïve 33% 0% N/A N/A
Memory All 70% N/A N/A N/A
Central/Transitional Memory 0% N/A 50% N/A
Central Memory N/A 57% N/A N/A
Transitional Memory N/A 12% N/A N/A
Effector Memory 82% 92% 19% N/A
Cell TypeBlood GALT
Time Point 1: EM vs CTM > 30-fold p < 0.0001
Time Point 2: EM vs CM 9-fold p = 0.002
EM vs TM > 86-fold p < 0.0001
82% 92%
0.005
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SCOPE2013: Leukapheresis
46
37
100367
78
29
98
0.01
Leuka TCM
Leuka TTM
Leuka TEM
Leuka DN (X5-R6-)
Leuka R6 (X5-R6+)
Leuka X5 (X5+R6-)
Leuka DP (X5+R6+)
On-Therapy
Hypermutants
stop
Viable
Subset Hypermutant (%)
Leuka TCM 50.0 (5/10)
Leuka TTM 11.5 (3/26)
Leuka TEM 100 (24/24)
Leuka DN (X5-R6-) 90.9 (20/22)
Leuka X5-R6+ 90.5 (19/21)
Leuka X5+R6- 0.0
Leuka DP (X5+R6+) 0.0
Treated during chronic infection > 15 years of therapy
97
100
13
40
84
42
97
99
0.01
% APD: 1.4%
Subset % Identical sequences
Leuka TCM 50.0 (2/4)
Leuka TTM 52.2 (12/23)
Leuka DN (X5-R6-) 0.0 (0/2)
Leuka R6 (X5-R6+) 0.0 (0/2)
Leuka X5 (X5+R6-) 75.5 (3/4)
Leuka DP (X5+R6+) 50.0 (3/6)
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Cellular Restriction Factors
Legend:
SLFN11: inhibits viral protein synthesis
Tetherin: blocks viral release
APOBEC3: Hypermutation; lethal mutations in viral DNA
MX2: blocks nuclear import of subviral complexes; blocks integration
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Conclusions
A large percentage of intracellular sequences, not represented in pre-therapy plasma, are clonal in nature.
These identical sequences are enriched during therapy and in more differentiated cells ie: effector memory.
This suggests that HIV persistence during effective therapy is driven in large part by the proliferation, differentiation and expansion of cell populations with sustained and durable regenerative potential.
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Acknowledgements
We acknowledge with gratitude the participation of all the patients in this study
Karolinska Institutet L. OdevallS. von Stockenström
VGTIN. Chomont
SAIC/NCIW. Shao
University of California, San FranciscoF. HechtE. SinclairP. BacchettiP. LewisP. HuntM. SomsoukH. HatanoS. DeeksL. EplingM. Kilian T. HoA. TanJ. CusterL. LoebR. HohL. PooleS. PillaiM. Abdel-MohsenA. Raposo
Westmead Millennium InstituteE. LeeB. HienerK. BartonM. LoganT. Cunningham
VRC/NIAIDD. DouekE. Boritz
Rega Institute, BelgiumN. FariaP. Lemey